A STRATEGY FOR FERTILITY SERVICES FOR SURVIVORS OF CHILDHOOD CANCER. by a Multidisciplinary WORKING GROUP convened by the BRITISH FERTILITY SOCIETY

Transcription

1 1 A STRATEGY FOR FERTILITY SERVICES FOR SURVIVORS OF CHILDHOOD CANCER by a Multidisciplinary WORKING GROUP convened by the BRITISH FERTILITY SOCIETY 1 Executive Summary 2 2 Background 3 3 Fertility Preservation in Childhood Cancer Care 5 4 Assisted Reproduction 13 5 Laboratory Aspects 17 6 Psychosocial Aspects 22 7 Ethical Aspects 25 8 Legal Aspects 27 9 NHS Framework References Summary of Recommendations 37 Appendices I. Puberty 39 II. Legal Aspects 41 III. General statement on Information Leaflets and Consent Forms with an example (Information Leaflet for Sperm Banking for Young People) 58 IV. List of Members of Working Group and Affiliations 61

2 Fertility Services and Cancer Survivors 2 1 Executive Summary Children being treated for cancer are increasingly likely to survive and many will grow to maturity. A significant number of these (15%) will have compromised reproductive function as a result of their cancer treatment. These numbers will increase so that impaired reproductive function becomes a significant public health problem for the future. Progress in long term ovarian tissue (cryo)preservation has led to the possibility, after they reach adulthood, of using gametes obtained from these children prior to treatment. This Report describes issues that need to be addressed. Gonadal tissue preservation by freezing (cryopreservation) is still an experimental procedure and research is required to establish the appropriate procedures and risk-benefit profile. There is no Health Service provision for tissue retrieval or storage. Organisation of future clinical care of candidates who wish to use their stored tissues will require multidisciplinary input. The relative risks and benefits of gonadal tissue retrieval and preservation have not been established. Uncertainty about technical procedures should be resolved by research protocols, which should be submitted to the appropriate research ethics committee. In contrast sperm storage for post-pubertal boys is a well established and proven technique which should now be considered routine. Psychosocial aspects of childhood cancer management are important and need to be dealt with by personnel appropriately experienced in psychology, paediatrics, oncology and reproductive medicine. Psychosocial support also needs to be accessible to survivors long after the successful completion of their cancer treatment. Meticulous documentation is required for adequate follow-up of all aspects of the oncology management. The processes of obtaining tissue for conservation, the cryopreservation technique and conditions of storage also need to be documented in a standard manner. The most efficient way of optimising all regimes for outcome of the cancer treatment and subsequent conception is by longitudinal and prospective data collection and review of the retained records of the various treatment details and these also need to be accessible for long term follow up. The Dept of Health has produced a Code of Practice for Tissue Banks. Paediatric Oncology and Assisted Conception Units will need to comply with these regulations by April, Only in this way can tissue containing immature gametes be used in the NHS in future. Liaison with a certified Tissue Bank may facilitate development of accreditable procedures for collection, transport and storage of tissue. A series of recommendations has been made to facilitate the development of a multidisciplinary service for these children and adults they will eventually become. They are directed at responsible organisations and individual units as well as the various arms of government. Appropriate responses will collectively ensure an effective outcome, which is the establishment of a properly funded, ethically sound and scientifically based service.

3 Fertility Services and Cancer Survivors 3 2 BACKGROUND Each year about 120 per million children in Britain suffer from cancer. Since the registration of children's cancer centres in 1977 (22 UKCCSG 1 centres) multicentre protocols have dramatically increased overall survival to 60-65%. It is estimated that currently 1 in 1000 young adults (25-35 years) have survived childhood cancer. However, the aggressive therapy required for cure may have longer term psychosocial and health-related consequences: impaired hormonal responses and future infertility. The extent of this infertility is unclear for three reasons: first, new cancer therapies are constantly developing; second, survival (and hence potential reproductive recovery) is further prolonged ; and third, new techniques have been developed in reproductive science. One of these, intracytoplasmic sperm injection (ICSI), has rapidly become established. Another, cryopreservation of immature oocytes and autotransplantation has been successful in sheep, leading to the birth of viable young. In the human, cryopreservation has been attempted and further application shows potential. Moreover, its promise of revolutionizing future fertility prospects for these children and young people, whose own fertility may be long in the future, is inspirational. In 1998 the Joint Council for Clinical Oncology of the Royal College of Physicians published a Working Party Report on the Management of gonadal toxicity resulting from the treatment of adult cancer. The idea behind the current Working Group arose during a meeting in Cambridge on "Ethical and Research Dilemmas for Children treated for Cancer" in December, In January 2000 the Royal College of Obstetricians and Gynaecologists published the Report of a Working Party on the Storage of ovarian and prepubertal testicular tissue. In August 2000 the British Fertility Society published their recommendations for Good Practice on the Storage of ovarian and prepubertal testicular tisse (Nugent et al., 2000). This was followed by symposia on the topic at the Teenage Cancer Trust Conference at the Royal College of Physicians in April, 2001 and the annual British Society of Paediatric Endocrinology meeting at Sheffield Hallam University in September, In October, 2001 the Royal College of Obstetricians and Gynaecologists held a meeting on Reproductive health services following childhood cancer. From all of these discussions it was evident that although paediatric oncologists had developed sophisticated management programmes, the children would either continue to be seen by their paediatric practitioners (who may be less aware of reproductive options) as adults or be passed on to practitioners of adult medicine who were ill prepared for the problems generated by these complex treatments. This applied particularly to the future management of their fertility, which could show any degree of compromise and at many different points of the hypothalamo-pituitary-target gland axis. There has also been considerable activity in adults taking ovarian samples for cryopreservation in an attempt to safeguard future fertility. That action was based on limited animal data, without the necessary understanding of how to reach the long term objective of achieving pregnancy in the human. Further, the support systems required for this sequence of events had not been defined. The British Fertility Society convened this multidisciplinary Working Group to define a strategy for developing reproductive health services for these survivors. It is grateful to the participants who responded so enthusiastically and embarked on a journey of exploration and mutual education. The members of the Working Group are listed in Appendix IV with their affiliations and areas of expertise. The Group met on seven occasions between December 2000 and January The Report describes current approaches to the treatment of childhood cancer. A protocol is laid out for creating a record that will be valuable for future fertility management. This is followed by discussion of the psychosocial, ethical and legal aspects (further elaborated in Appendix. II). The issues in children are more complex than in adults and there is a clear need for separate discussion of the immediate curative treatment events and those directed at conservation of future fertility potential after effective treatment. Recent government regulations on tissue cryopreservation have tightened storage procedures for immature gametes/tissue. These are reviewed and will need to be considered carefully by Assisted Conception Units. The current approaches to management of fertility in those who do and those who do not have gametes or tissue cryopreserved are described.

4 Fertility Services and Cancer Survivors 4 Finally, the framework for cancer care in the National Health Service has changed markedly and this is briefly described. Those practising in paediatrics need to be aware of progress in reproductive medicine and assisted conception in particular. Those working in secondary and tertiary level fertility units need to be aware of the major advances in paediatric oncology and the nature of the potentially compromised fertility of their newly adult patients. There needs to be considerable sensitivity to the psychosocial consequences in these young people, who should be regarded as having a chronic illness, rather than entirely "cured" or free of disease. Similar issues are raised in the fertility management of adults with cancer, those having gonadotoxic therapy for other conditions or those likely to experience an early menopause for genetic or other reasons. The latter two problems may usefully also be considered in a similar manner.

5 Fertility Services and Cancer Survivors 5 3 Summary FERTILITY PRESERVATION IN CHILDHOOD CANCER CARE Progress in long term reproductive tissue preservation has led to the using gametes obtained from children prior to treatment, when they reach adulthood. Research into improving methods of tissue preservation is required. Issues of consent, long term record maintenance, multidisciplinary communication and funding need to be resolved. There needs to be extensive documentation, so that on the long term, fertility treatment can be optimised. The data can be used for research to improve outcome and better understand the consequences of cancer treatment. This chapter reviews the details that should be considered in trying to achieve these objectives. Children treated for cancer are increasingly likely to survive: the overall chance of cure is 65% and for specific cancers e.g. leukaemias lymphomas and germ cell tumours, nearly 100%. A significant number of survivors has grown to maturity, each having an average of a further 68 years of life ahead, compared to 10 years for each adult cancer patient; some even have offspring. Some 15% will have a high risk (95%) of early and irreversible gonadal failure, while others may have lesser degrees of compromised reproductive capacity as a result of their cancer treatment (Wallace et al., 2001). Different cancers are associated with different risks of future fertility compromise and these may be classified as shown in Table 1. Those most at risk are often those most intensively treated with consequent multiple toxicities (for example those requiring a Bone Marrow Transplant, BMT). Nevertheless survival is still increasing - BMT survival is up to 60% - so that impaired quality of life and reproductive function become a significant concern. Males are more susceptible to subfertility following chemotherapy than females, but females may be at risk of premature menopause. Treatment with some chemotherapeutic agents is particularly likely to result in gonadal toxicity. Those most likely to cause germ cell damage are shown in Table 2. These are toxic agents, including alkylating agents, specifically cyclophosphamide, procarbazine and cis-platinum, lomustine/carmustine (proven dose-dependent toxicity) Conditions other than cancer which may be treated by chronic, lower dose administration of cytotoxic drugs. Children and young people suffering from these non-cancerous conditions may also be potentially at risk of gonadal damage and be suitable for fertility conserving measures. The new challenge facing professionals in many different disciplines is how the childís wellbeing can be protected at a time when curative treatments to avert mortality are juxtaposed with options for protecting fertility. New and competing issues and options are raised for the child and the family to consider. There are already a number of options for managing potential fertility problems: there may be natural restoration of the individualís fertility over time in the male (Meistrich et al.,1989). attempts may be made to protect or initiate restoration of reproductive function by the use of hormonal or other treatment before or after gonadotoxic chemotherapy. harvested and cryopreserved gametes may be used in the future, already used for many years for the adult male, but not yet efficiently for the female. germ cells and tissues containing immature gametes may be collected, stored and manipulated with the ultimate aim of enabling an individual to become a parent of a genetically related child; this has only so far been successful in animal models Except in the case of the post-pubertal and competent male 1, where sperm banking prior to therapy is recommended, there is uncertainty over the most effective methods of attempting to maintain or restore an individualís fertility, each other method being experimental with unknown efficiency and potential advantages, disadvantages and risks. Where there is uncertainty amongst professionals, there are 1 General Medical Council (1998) Seeking patients' consent: the ethical considerations, describes Gillick competence

6 Fertility Services and Cancer Survivors 6 particular difficulties in advising patients and parents on what is likely to be the most appropriate course of action. There are special concerns in relation to the treatment of children because of the need to consider the extent to which they are able and/or wish to participate in decision making. The importance of involving children in discussion and giving them the support they need to play a meaningful role in treatment decisions is well recognised, by both professional (Royal College of Paediatrics and Child Health) and legal (Children Act, 1989; UN Convention on Rights of the Child, 1990) bodies, although there is a need to consider carefully how this may best be achieved. However, there will be cases where decisions are made on the childís behalf, raising problems of deciding what is likely to be in the childís best interests both in the short and the long term, particularly where the issue at stake is a quality of life rather than quantity of life choice and the nature of the intervention an experiment governed by separate ethical constraints (Declaration of Helsinki, Edinburgh, 2000). Table 1 Risk of future fertility compromise associated with different cancers Low Medium High Acute lymphatic leukaemia Acute myeloid leukaemia Total body irradiation Soft tissue sarcoma Stage I Wilms' tumour Localised radiotherapy: Germ cell tumours with Hepatoblastoma pelvic or testicular gonadal preservation and Osteosarcoma High dose chemotherapy no radiotherapy Soft tissue sarcoma >Stage I "conditioning" for bone marrow/ Brain tumour Neuroblastoma stem cell transplant surgery only Non-Hodgkin's lymphoma Hodgkin's disease: alkylating cranial irradiation Hodgkin's disease: agent-based therapy (males) "hybrid therapy" alkylators only (females) Brain tumour: craniospinal radiotherapy +/- chemotherapy cranial irradiation (>24 Gy) Ewing's sarcoma (suspected) Soft tissue sarcoma: metastatic Notes: 1 There is insufficient evidence to be definitive, so this represents the best educated guide. 2 This Table may be used as a guideline on which to base fertility counselling at the onset of treatment relating specifically to gonadotoxicity. The development of strategies for minimising the effects of cancer treatment on future fertility is still at an early stage. Some interventions under consideration can proceed within already established frameworks designed to deal with some of the issues: e.g. the storage and use of mature gametes is regulated in the United Kingdom by the Human Fertilisation and Embryology Authority (HFEA). However such a regulatory authority was not designed with children in mind. There may therefore be a need for reappraisal and perhaps amendment of this framework to offer children the same opportunity and protection as adults. Other types of intervention, such as the storage and use of germ cells and tissue, currently fall outside the remit of the HFEA, because they are considered not to be or contain mature gametes. Since these techniques are at a preliminary stage of development we consider that they should be governed by the principles applicable to research unless or until there is proven therapeutic benefit. Tissue stored for possible therapeutic use will be controlled by regulated tissue banks, whereas tissues stored for research fall outside those regulations. If it is intended in the future to return such tissue, or oocytes derived from it, to the body, it should be stored in compliance with the relevant regulatory regime. In enabling the best advice and care to be given to children embarking on cancer treatment and their parents we consider that the following issues are of crucial importance:

7 Fertility Services and Cancer Survivors 7 rigorous review of procedures and evaluation of results obtained. multidisciplinary work both in the care of the child and in research. continuing multidisciplinary dialogue and the exchange of experience and expertise. collection of information on a long term basis ñ involving follow-up of patients with the agreement of the patient and family and perhaps central collection of data. the maintenance of high standards in the collection and storage of tissue and record keeping. well-designed, performed and documented research with rapid dissemination of results. In the aim of successful germ cell storage, pretreatment consideration of germ cell harvest and storage is in the best interests of the child. Table 2 Gonadotoxicity of Chemotherapeutic Agents Group Alkylating agents Vinca alkaloids Antimetabolites Proven Gonadotoxicity Cyclophosphamide Chlorambucil Melphalan Busulfan Carmustine Lomustine Mechlorethamine Procarbazine Cisplatin Vinblastine Cytosine arabinoside We recommend that clinical and research practice in this area develop in a phased manner: 38 Develop a consensus of treatment-related risks of germ cell damage. 39 Develop a consensus of risks to the child associated with methods of germ cell harvest. 40 Develop methods of prospective data collection aimed at registering germ cell tissues stored, collection methods and conditions of storage. In addition, a register of patients at risk of sub-fertility (including those who choose not to undergo harvesting procedures) should be established. 41 Monitor success rates for the use of stored germ cell material, fertility rates of all those registered and organise the follow-up of any offspring. There are many aspects of management that need to be considered in treating childhood malignancy. Keeping in mind the patient's long term fertility prospects requires attention to many details prior to the commencement of any therapy. The response will be determined by the patient's maturity, hence ability to consent. Arrangements for gamete storage are now complex and meticulous documentation 2 is essential. These records will be the basis of management in a Late Effects Clinic following successful therapy and subsequently in an Assisted Conception Unit. Careful liaison with the centre storing any germ cells or gametes (Assisted Conception Unit or Tissue Bank) will need to be established. 2 Long term record storage will be required for follow up and research. However the issue of informed consent and cancer registries has not yet been resolved. The Health and Social Care Act, Section 60, established in August, 2001 a Patient Information Advisory Group (Statutory Instrument 2001/2836), which will consider what data can be used for cancer registration without informed consent. The recommendations of this group will be relevant and significant.

8 Fertility Services and Cancer Survivors 8 FEMALES Retrieval, cryopreservation and storage procedures could be considered in young children who have potentially more ovarian follicles to harvest. However, the operation is also potentially more hazardous, possibly requiring laparotomy rather than laparoscopy, and removal of a relatively larger amount of ovarian tissue.. The smallest children have a larger ovarian pool of oocytes and are those who are most likely spontaneously (perhaps temporarily) to resume cyclical ovarian function. In view of this and the wider ethical debate, tissue cryopreservation is not currently recommended as routine for these children; it remains a research procedure. Specific research studies in this area should be carefully reviewed by the appropriate ethical committee, which should be fully informed of the complex debate and have recourse to appropriate legal advice. Specific guidance should be requested on tissue storage and experimentation. Parents/families who specifically request information on this issue should have these principles explained. Psychosocial support should be offered for their discussions about fertility preservation. These youngsters may be recognised as "Gillick competent" if sufficient time and explanation are given. If their gonads may be capable of producing mature gametes, ovarian stimulation and oocyte collection may be considered in post-pubertal females although at present mature oocyte storage and subsequent use has limited success. Although these procedures are established, they may be inappropriate because of the length and intensity of a stimulated cycle and its associated risks. Alternatively, cryopreservation of samples of the ovarian cortex could be considered. General Inclusion Criteria for offering Gonadal Tissue Cryopreservation The chance of survival, the risk of subfertility and the age of the patient need to be taken into account. However, the following categories should be included: 38 those having high dose therapy involving alkylating agents or total body irradiation (TBI). 39 those having direct pelvic irradiation. 40 those having cycles of MOPP/CHOPP for Hodgkin's disease. 41 those who are Gillick competent 42 those who are HIV and Hepatitis B and C negative General Exclusion Criteria for offering Gonadal Tissue Cryopreservation All subjects: 38 having an excessive surgical risk such as a bleeding diathesis 39 who are not Gillick competent (unless their parents can consent to storage of tissue in the child's best interest). 40 having primary or secondary ovarian malignancy, except where the ovaries are being removed anyway, the risk being less than that of two separate procedures. This tissue could possibly be used in the future for in vitro follicle culture 41 the procedure would cause excessive delay in curative treatment Decisions should be individualised when: 38 there is a known familial genetic predisposition to disease 39 the patient is a carrier of viral infection (HIV, Hepatitis B or Hepatitis C) as separate storage facilities are required. Psychosocial support should comprise: 1 independent counselling by practitioner(s) with paediatric, endocrinological, reproductive medicine, psychological, mental health or combined experience in assessing competence and knowledge of the issues. 2 Information, separate from that provided by the oncologist and preferably given over several days. 3 written information that has been externally reviewed and also piloted. 4 some assessment and statement of competence. Seeking Consent

9 Fertility Services and Cancer Survivors 9 There should be structured interviews and the consent should involve if possible a trained psychosocial specialist, paediatric oncologist and reproductive medicine specialist/scientist in establishing competence and understanding. If appropriate, this could include: 42 written consent to obtain germ cell tissue in the female 43 written consent to cryopreserve the germ cells or mature gametes, as required by the HFE Act, written consent to dispose of the tissue in the event of death or incapacitation. Without research on tissue obtained in this way there will be no information available on which to base future management. Lack of research increases the risk of failure when there is a need to use the tissue for future fertility. After cryopreservation of a tissue sample, up to 10% of it could be thawed for histological examination to determine whether the frozen tissue is likely to be in a satisfactory condition for future use by the patient. Such confirmation would indicate good practice and would be a sound basis on which to base counselling. The thawed tissue could be used for research. It would be helpful to try and obtain: a written agreement to offer part of the tissue obtained for research. a written agreement to donate the tissue for research in the event of death. a statement of understanding of the experimental nature of the procedures and their potential hazards. an acceptance of the need to be screened for HIV, Hepatitis B and C. a statement that consent to treatment cannot be given at that time and that separate written consent may be obtained from the individual at a later date after proper counselling in an Assisted Conception Unit. a statement that future NHS or private fertility treatment is not assured. parents/supervising medical staff/g.p.s should be asked to inform the laboratory in the event of death of the patient. Prior to gonadotoxic treatment the patient should undergo: recording of height, weight and body mass index (BMI). pelvic/vaginal ultrasound for ovarian volume, activity/cycle timing and uterine dimensions, serum sampling for LH, FSH, progesterone, oestradiol, testosterone, inhibin and thyroid function tests (cycle timed when appropriate), HIV, Hepatitis B and Hepatitis C screening laparoscopic surgery for ovarian biopsies or removal of a single whole ovary (to prepare ovarian cortical slices for cryopreservation) according to predetermined criteria before chemotherapy or radiotherapy is administered. After treatment There should be a record of: the decision and clinical outcome in all patients counselled any data on the quality of germ cell tissue sample and gametes obtained any peri-operative complications of tissue retrieval. counselling given. the time taken from counselling to tissue retrieval. Further, 1 regular contact with the storage facility should be maintained. 2 a register of paediatric patients, with appropriate consent, should be initiated through UKCCSG. 3 endocrine assessments should be made in collaboration with the Late Effects Clinic and later with an Assisted Conception unit.

10 Fertility Services and Cancer Survivors 10 All female patients, when able to understand the implications, and including existing adult survivors of childhood cancers, should be advised of the potential for: spontaneous pregnancy, and possible complications e.g miscarriages/premature birth following uterine irradiation. considering oocyte or embryo cryopreservation as a precaution against an early menopause, recognising the difficulties with this procedure. MALES likely good health of any children born (although follow up is still short). access to oocyte donation programmes surrogacy, if uterine function is affected. being referred to an NHS fertility clinic for assessment / advice. side effects of cancer treatment (eg cardiotoxicity/renal problems) that may impact on pregnancy. psychotherapeutic support in developing peer relationships etc. 38 Sperm banking should be offered to post-pubertal males (if consent can be given under the terms of the 1990 Act) regardless of diagnosis and treatment. 39 Currently no surgical procedure for germ cell retrieval is established or recommended in pre-pubertal males ( testicular biopsy is feasible for adults) 40 Any studies in this area need careful consideration and independent approval by an appropriate research ethics committee. 41 Alternative gonadal protection strategies are currently being explored in primates. 42 Psychosocial support should be offered for their discussions about fertility preservation. If a boy is Gillick competent he should be offered the opportunity to produce a semen sample. If he is noncompetent, it is inappropriate to approach him under the HFE Act; as without written informed consent, the sperm cannot be stored. A leaflet should be given in advance of counselling (see Appendix III). Independent counselling should be given by a dedicated clinical nurse/practitioner with reproductive medicine experience. There may be a need to teach masturbation. 1 It is desirable to obtain several pretreatment donations. The date and result of semen analyses must be clearly recorded in the medical notes. Although in the past, discussion and donations have been made over several days whilst commencing cancer treatment, there is evidence in rats that treatment is associated with sperm DNA damage, stress response gene expression in the testis, embryo loss, fetal malformations and second generation effects (Qiu, Hales and Robaire,1992). These effects suggest that sperm banking should be completed prior to commencing anti-cancer treatment. Even apparently poor samples may later be suitable for intracytoplasmic injection (ICSI). If a semen sample cannot be obtained, electroejaculation under anaesthesia may be offered as an alternative to testicular biopsy. Prior to biopsy, there may be benefit in performing a baseline ultrasound examination of the testes as scars may later be evident. As there are anxieties about the increasing rate of testicular cancer in young men, an ultrasound image taken prior to a biopsy may help in interpreting later images. Psychosocial support should comprise: independent counselling by practitioner(s) with paediatric, endocrinological, reproductive medicine, psychological, mental health or combined experience in assessing competence and knowledge of the issues. information separate from that provided by the oncologist and preferably given over several days. written information that has been externally reviewed and also piloted. some assessment and statement of competence. giving a leaflet explaining sperm donation (see Appendix III ) followed by discussion and checking understanding. The patient should understand:

11 Fertility Services and Cancer Survivors 11 that he has sole responsibility for making all decisions about fertility preservation. it is voluntary and he can decline. it is confidential (parents need not know of any donations). what happens if he "fails" to produce a semen sample and the reasons for failure. the estimated chance of infertility. that he is not consenting to future treatment at this stage. potential for future fertility treatment for his partner including intracytoplasmic sperm injection (ICSI). the difference between potency (which is usually preserved) and infertility. the consent forms. Seeking Consent There should be structured interviews and the consent should involve a trained psychosocial specialist, paediatric endocrinologist/oncologist and reproductive medicine specialist/scientist in establishing competence and understanding (consistent with the HFE Act, 1990). If appropriate, this could include: written consent to storage : HFEA forms should be used [HFEA(006)]. written consent to the use of part of the sample for research, if appropriate and freely given. written consent to disclosure of the sample quality to the referring practitioner. written consent to disposal on death or incapacitation. written consent to donation for research, if appropriate, a written statement that storage of gametes does not mean that future NHS or private treatment can be assured. Prior to treatment Males should undergo: 40 pubertal assessment with recording of height and weight. 41 serum sampling for LH, FSH, testosterone and inhibin. 42 recording of the diagnosis and stage of disease. 43 recording of potentially gonadotoxic treatment to date (cumulative dose). After treatment: 5 the follow-up record should have the outcome and cumulative total doses of gonadotoxic treatments updated. 6 the patient should be offered a chance to donate semen for analysis and banking if specimens have not previously been stored. 7 if sperm samples have not been stored prior to treatment, he should be encouraged to provide samples beginning at least 3 months after the conclusion of treatment to reduce the risk of storing damaged sperm. 8 he should be advised about the possible need for ICSI. If he requires fertility advice or is seeking fertility treatment he should be referred to an Assisted Conception unit for discussion. Conclusions 1 Children being treated for childhood cancer are increasingly likely to survive. 2 The development of gonadal tissue cryopreservation creates the opportunity to elaborate long term strategies. 3 Systems must be established to foster progress from the presentation of the child with cancer through counselling, with or without cryopreservation of the gonadal tissue, to spontaneous or assisted conception. 4 The initial clinical details including endocrine status should be documented. 5 The issues that the subject understands need to be identified and recorded.

12 Fertility Services and Cancer Survivors 12 6 All written information should be appropriately reviewed and piloted. 7 The provision of written explanatory material should be documented. 8 The fact that psychosocial support has been provided, independent of those providing the oncological treatment, should be recorded. 9 Whether a child is Gillick competent or incompetent must be recorded. 10 Consent for storage of tissue and any consent for its use in research, each after appropriate discussion, should be recorded on specifically designed forms. 11 The decisions about disposal of tissue or its use for research, in the event of death, should be recorded. 12 The need for research should be recognised at all points. 13 There should be prospective medical and mental health research at all stages, so that outcome may ultimately be optimised. 14 Oncology Units need to develop links with Assisted Conception Units. 15 Legal aspects of consent for ultimate use of the stored samples need to be developed (cf Chapter 8). 16 The Tissue Banks Code of Practice regulations must be complied with by all Units (cf Chapter 5). 17 Patient commitment and the intense multidisciplinary nature of treatment should be recognised. 18 There are implications for long term health surveillance of patients and their offspring as well as recording data on interventions. 19 Treated women should be followed up at least to their menopause. 20 All offspring should be followed up long term. Recommendations Oncology Units should ensure that: 1 all competent males who can produce semen have the opportunity of discussing the preservation of their fertility with an appropriately trained person. 2 all competent females have the opportunity of discussing the preservation of their fertility by conservation of a sample of gonadal tissue or oocytes with an appropriately trained person prior to gonadotoxic therapy or removal of ovarian tissue. 3 the parents of non-competent children are given the opportunity of discussing the issues relating to their children's gonadal tissue conservation and agreeing an appropriate course of action. 4 in addition to obtaining consent for gonadal tissue conservation, where appropriate, the rationale and need for relevant research should be explained. An attempt should be made to seek consent to use a part of the tissue for research, but participation in the programme must not be contingent upon taking part in the research. 5 documentation of the oncology management is standardised and held in such a way that the data are accessible when required which may be 30 years later. Oncology Units and Assisted Conception Units, storing gonadal tissue should ensure that they develop: 6 full protocols for long term record keeping. 7 consent forms for obtaining tissue. 8 consent forms for the use of tissue for research. 9 consent forms for the use of tissue for research. 10 written material to explain the implications of consent to take tissue, store it and use it in research. Oncology and Assisted Conception Units should ensure that: 11 when treatment of a child has been successfully completed, there is liaison between the two Units to provide opportunities for explanation and support during adolescence and adulthood prior to the potential use of the preserved tissue (cf Chapter 4). 12 a central registry of all patients completing paediatric oncology treatment is established, so that data can be stored for research and ultimate use in treatment by an Assisted Conception Unit. 13 they use a minimum data set for subsequent use in an Assisted Conception Unit. 14 they use a minimum data set for long-term follow-up so that research can ultimately establish the value of the treatment, biopsy, storage and psychological support regime. 15 these minimum data sets should be developed at a national level.

13 Fertility Services and Cancer Survivors 13 Summary 4 ASSISTED CONCEPTION Ovarian tissue cryopreservation is an experimental procedure without documented success. As yet, there is no Health Service funding available for tissue retrieval or storage. Research is required to establish the effective procedures. Organisation of future clinical care of candidates who wish to use their stored tissues will require multidisciplinary input. CURRENT PRACTICE Women requesting measures to retain fertility prior to chemotherapy or radiotherapy have the following options: embryo cryopreservation: stimulated IVF cycle and fertilization of the harvested oocytes with sperm of the husband/partner or donor and storage of the resulting embryos. This technology is well established and has proven success but not many embryos can be obtained from one stimulation cycle. It is only applicable to adult women in a stable relationship. oocyte cryopreservation: stimulated IVF cycle and storage of the harvested oocytes for later thawing and fertilization. This technology has proven but limited success and not many eggs can be obtained from one stimulation cycle. It is only applicable to post-pubertal women. ovarian tissue cryopreservation: requires an operative procedure (usually laparoscopic) to harvest ovarian tissue, which contains immature oocytes, but avoids ovarian stimulation. This is an experimental technique with no proven success in humans and limited success in animal models. It is applicable both to prepubertal and post-pubertal females. ovarian suppression prior to chemotherapy: use of progestogen or GnRH analogues is of unknown value oophoropexy prior to radiotherapy: appropriate for only a very few patients, requires an operative procedure (laparoscopy) to move ovaries out of the field of pelvic radiotherapy Ovarian tissue cryopreservation Women undergoing therapy for malignancy, where there is ìintention to cureî, and a high likelihood of therapy-induced premature ovarian failure, are candidates, provided the procedure does not carry excessive risk, if they: 2 have solid tissue malignancy (with no sign of spread e.g. breast carcinoma, osteosarcoma). Reproductive cancers (breast, ovary) need special consideration as some breast cancer may be oestrogen-dependent with a potential risk from gonadotrophin stimulation, ovarian cancer with storage of the contralateral ovary in ovarian cancer carries a risk of malignancy recurrence if regrafted. 3 have haematological malignancy. There may be a risk of further disease on regrafting ovarian tissue. It may arise from malignant cells cryopreserved in the tissue initially obtained. Women may also request ovarian storage if: 38 they have non-malignant conditions and are undergoing chemotherapy, where cytotoxic agents may reduce fertility e.g. severe lupus.

14 Fertility Services and Cancer Survivors have a family history of premature ovarian failure. The woman may request tissue storage at a relatively young age, having no partner, to overcome their possible infertility later in life. 40 if, not being in a relationship, wish to store tissue whilst young to allow future childbearing through assisted conception without age-related loss of fertility and risk of aneuploidy ñ ìsocial ì requests. Current regulation of storage and use Storage of ovarian or testicular tissue, that contains or may contain mature gametes, requires a storage licence under the Human Fertilisation and Embryology Act (1990). Storage without a licence is a criminal offence. Similarly, therapeutic use of stored gametes, or maturation of immature gametes in vitro for the purposes of treatment, requires a licence from the HFEA, and may only be undertaken in premises licensed by the HFEA. Posthumous use of gametes requires appropriate antemortem written consent in accordance with the HFE Act (1990) and the HFEA Code of Practice. Thus autografting of ovarian tissue does not require an HFEA treatment licence. Experiments to mature oocytes in vitro without a view to fertilization or replacement for therapy, i.e. for research, does not require an HFEA licence. However, any attempt to fertilise oocytes in vitro for the purposes of research or therapy will fall within the remit of the HFEA. All storage of mature oocytes requires a licence. Ovarian tissue that does not contain mature oocytes is not subject to the HFE Act ñ but it does fall within the remit of the Medical Devices Agency Tissue Banking inspection system. Research proposals must receive approval from an LREC. Consent for use of tissue in research must be obtained. Posthumous use requires antecedent consent from the patient to ìgiftî the tissue for research. Preparation of the candidate Counselling: individuals requesting fertility preservation require counselling and access to adequate facilities. Advice about the relevant aspects of both the oncology and assisted conception must be given. Screening: exclusion of transmissible disease (HIV, Hepatitis B and C) and the use of quarantine banks for storage will be advised by the HFEA. Screening may not be possible within the time limitations imposed by the imminence of treatment, so separate storage would be necessary until clearance has been effected. That carries an additional requirement for counselling. Consent: specific consent is required for any procedure that fallsunder the HFE Act. Collection of ovarian tissue Collection of ovarian tissue in children requires competence in laparoscopy and should ideally be carried out by a paediatric surgeon. In adult women it is likely to be done laparoscopically by a gynaecologist. Consent for the operative procedure is required and this must be the responsibility of the surgeon. It may be obtained separately from the counselling and consent for tissue storage. Collection of ovarian tissue may be undertaken at the time of operation for the primary malignancy or at insertion of a Hickman line to avoid repeated admission and anaesthesia. It is as yet uncertain how much ovarian tissue should be removed for storage and what effect removal of that volume of tissue may have on future natural fertility if therapy does not sterilize. It has not been established whether multiple small biopsies (which might contain insufficient follicles), a portion of an ovary or a whole ovary should be removed. Storage

15 Fertility Services and Cancer Survivors 15 A system should be implemented for maintaining contact with those patients surviving treatment. It could be similar to that used for HFEA regulated semen storage. A national registry of stored ovarian tissue is recommended Funding Funding for these novel procedures is required. This must cover the collection procedure and longterm storage costs. Charging patients already under the stress of cancer treatment is inappropriate. Covering the costs of fertility preservation under the oncology budget should be explored. The elements of obtaining and cryopreserving the samples should be funded separately from storage, which may need to be long term. Research Research into the processes of tissue collection, preparation, cryopreservation and storage are essential if stored ovarian tissue is ever to be used successfully. Ovarian tissue storage should only be undertaken within a research setting until pregnancy outcome data from cryopreserved samples are available. Ideally some tissue should be taken and stored for research at the same time as tissue is obtained for potential treatment purposes. Information about both research and treatment should be provided during counselling. Separate consents are required. FUTURE FERTILITY USE Only a small proportion of tissue samples stored are likely to be utilized for fertility. Among male survivors of cancer, the take-up of stored sperm samples is surprisingly low. There is evidence that survivors of childhood cancers have low rates of marriage. It is possible that one reason for this is their perceived infertility. Cryopreservation would improve survivorsí self-esteem and their chances of long-term relationships. Fitness for pregnancy: some chemotherapeutic agents have cardiac or renal toxicity, and prepregnancy review by a ìlate effectsî specialist is recommended. Patients receiving chemotherapy for non-malignant disease may have other issues e.g. renal involvement in systemic lupus erythematosis or heritability of sickle cell disease. These patients should be seen by a Consultant Obstetrician. Uterine function: it is well recognised that uterine irradiation may affect subsequent pregnancies with risks of miscarriage, premature delivery and fetal growth retardation. Implantation and endometrial response may be impaired. Patients who have received uterine irradiation (e.g. TBI pre-transplant, Wilms' tumour) may require surrogacy. Follow-up of children born from the new technologies is recommended 4 Conclusions 1 Embryo cryopreservation is an established procedure. 2 Oocyte cryopreservation has had limited application. 3 Ovarian tissue cryopreservation is an experimental technique; no successful pregnancy has yet been reported in the human, but preservation is intended to create future opportunities for these patients as techniques develop. 4 There are conditions in which ovarian tissue cryopreservation may be valuable. 5 Different regulatory conditions apply to storage and use of cryopreserved ovarian tissue. 6 Technical aspects of ovarian tissue retrieval and storage have not been established. 7 NHS funding for gonadal tissue retrieval or storage has not been defined. 8 Female patients having tissue stored will ultimately require Consultant Obstetrician review before using their stored samples is contemplated. 9 All children born after use of stored tissue should be followed up. 4 A Central Registry for paediatric data is being considered by the UKCCSG

16 Fertility Services and Cancer Survivors 16 Recommendations 1 Oncology and Assisted Conception Units should systematically develop research on human ovarian tissue retrieval and storage. 2 Assisted Conception units should have prospective patients evaluated by a Consultant Obstetrician with multidisciplinary input when contemplating use of their stored tissue. 3 Late Effects Clinic should make their patients records available to the relevant Consultant Obstetrician when requested. 4 Representative Bodies should jointly establish a consortium containing a paediatric oncologist, Late Effects specialist, reproductive medicine specialist, clinical scientist, obstetrician and epidemiologist, who should design and carry out follow-up studies of children born after using these procedures. 5 Appropriate Health Service funding should be available for these patients.

17 Fertility Services and Cancer Survivors 17 5 Summary LABORATORY ASPECTS Cryopreservation and storage of mature sperm, oocytes and embryos fall under the aegis of the Human Fertilisation and Embryology Act and the Code of Practice, whereas cryopreservation and storage of immature oocytes and sperm, as well as ovarian and testicular tissue, are regulated by the Dept of Health's Code of Practice for Tissue Banks. Storage facilities, including Paediatric Oncology and Assisted Conception Units, will need to comply with these regulations by April, Only in this way will the use of immature gametes be assured after that date. Liaison with a certified Tissue Bank by Paediatric Oncology and Assisted Conception Units may facilitate compliance by development of procedures for collection, transport and storage of tissue. Protection of gametes and germ cells in situ from the effects of cancer therapy, while a future possibility, is not currently a successful option, hence current efforts to preserve fertility are focussed on the removal and storage of tissue before therapy commences. Different concerns are raised by the cryopreservation of spermatozoa and oocytes in mature or immature stages, and the regulations pertaining to their storage also differ, so storage for males and females will be dealt with separately. CRYOPRESERVATION AND STORAGE FOR MALES Sperm Mature sperm (interpreted by the Human Fertilisation and Embryology Authority (HFEA) as a haploid male gamete which is able to take part in fertilisation) can be cryopreserved using simple laboratory procedures. Under normal circumstances, the ejaculate is diluted with an appropriate cryoprotectant solution, loaded into labelled vials or straws, and suspended in the vapour above liquid nitrogen for around 15 minutes until the contents are frozen and equilibrated at around -70qC. The containers are then plunged into liquid nitrogen for long term storage. Commonly an average of about half of the sperm survive the freezing and thawing procedure, although this is highly variable among individuals. The widespread availability of ICSI now makes it worthwhile to cryopreserve almost all semen samples, even those where sperm have extremely poor characteristics of count, motility and morphology, with reasonable chance of an ultimately successful outcome of later fertility treatment. The cryopreservation of mature sperm is regulated by the HFEA (see below). Immature sperm and immature testicular tissue The cryopreservation of immature sperm, germ cells or immature testicular tissue for boys in whom mature sperm are not produced has not yet been established as a successful clinical treatment. Research is ongoing in this area (Brinster and Avarbock 1994; Schlatt et al, 2000; Brook et al, 2001).